This invention relates to a novel formulation for fat-soluble drugs (including tocotrienols, tocopherols, vitamin A, D and xcex2-carotene) which self-emulsify in the presence of an aqueous medium with little agitation. More specifically, the invention is concerned with the formulation of a new dosage form for fat-soluble drugs in the form of a soft-gelatin capsule which forms emulsion instantly when the contents are released and mixed with our gastrointestinal fluid. Since emulsions are known to increase absorption of fat-soluble drugs, the dosage form thus provides higher and more consistent drug absorption. The success of the invention lies in its ability to self-emulsify in the gastrointestinal tract and comprised a suitable mixture of the drug with an appropriate oil and an appropriate surfactant system.
Fat-soluble drugs such as tocotrienols and tocopherols are absorbed in the same pathway as other nonpolar lipids such as triglycerides and cholesterol (Kayden and Traber, 1993, J. Lipid Res., 34:343-358). Liver produces bile to emulsify the tocopherols incorporating them into micelles along with other fat-soluble compounds to facilitate absorption. Therefore, dietary fat, which promotes production of lipases and bile, is essential for absorption of vitamin E. However, if dietary fat is insufficient to stimulate adequate bile secretion, or bile secretion is affected by some pathological conditions such as biliary obstruction, then absorption of the fat-soluble drugs will be erratic and low. Also, it is known that absorption of fat-soluble drugs tend to be erratic and low when taken fasted or on an empty stomach.
Emulsions have been known to improve absorption of oil soluble drugs. However, conventional emulsions are not a preferred dosage form since they are bulky, have shorter shelf life due to stability problem and are less palatable. In recent years, there is a great interest in self-emulsifying drug delivery systems (SEDDS) due to the many advantages offered by these kind of systems which include enhanced bioavailability, improved reproducibility of plasma profiles and reduced inter- and intra-subject variability. SEDDS are formulated in the absence of water by mixing oil with one or more suitable non-ionic surfactants. Drugs, which have adequate solubility in the oil/surfactant blend, can be incorporated into the systems. Upon dilution or in vivo administration they form fine oil in water emulsions spontaneously with gentle agitation.
In the present studies it is discovered that the bioavailability of xcex4-, xcex3- and xcex1-tocotrienols in palm olein and soybean oil mixtures were approximately 2.7, 2.8, 1.9 times and 2.2, 2.1, 1.6 times that of tocotrienols in medium chain triglyceride mixtures in rats respectively. This could be attributed to the long chain fatty acid of palm olein and soybean oil, which promote the absorption of tocotrienols into the lymph. A number of studies (Sieber et al, 1974, Xenobiotica 4, 265-284 and Palin et al, 1984, J. Pharm. Pharmacol. 36, 641-643) have shown that long chain fatty acids ( greater than C14) (which are present in the palm oil and soybean oil), tend to increase absorption of oil soluble drug through the lymphatic system.
The present studies led to the discovery of a novel formulation by suitably blending palm olein or soybean oil with an appropriate surfactant mixture of Labrasol (caprylocaproyl macrogolglycerides) and Tween 80. The Labrasol to Tween 80 ratio was between 9:1 and 7:3. The above system could self-emulsify easily in water with gentle agitation (such as movement of stomach/small intestine). Therefore, the formulation need not be prepared like a usual emulsion, which is bulky and not palatable. Instead, the mixture is filled in a soft gelatin capsule. In stomach, the capsule wall dissolves and disintegrates and releases the contents, which will readily form an emulsion. Emulsions will give a bigger surface area for absorption and subsequently increased the absorption of fat-soluble drugs like tocotrienols. It was also demonstrated that the self-emulsifying system comprising the palm olein or soybean oil blended with the surfactant mixture could self-emulsify readily with water, when incorporated with fat soluble drugs including tocotrienols, tocopherols, vitamin A, vitamin D and xcex2-carotene. In addition, the novel formulation could increase the absorption of xcex4-, xcex3- and xcex1-tocotrienols by approximately 2 to 3 times that of the normal conventional soft gelatin capsule formulation when evaluated using twelve healthy human volunteers. The ratio of the surfactants to the oil and drug mixture was also demonstrated to be very important for enhanced drug absorption. For example, it was demonstrated that equal proportions of surfactant to the drug and oil mixture gave poor absorption whereas one part of surfactants to five parts of drug and oil mixture produced not only good self-emulsifying properties but also optionally enhanced drug absorption.
In conclusion, the studies had optimized three important formulation variables to achieve a superior product with enhanced bioavailability/absorption, namely
(i) use of palm olein and soybean oil as the vehicle for fat-soluble drugs like tocotrienols, which help to enhance absorption;
(ii) addition of a suitable combination of Labrasol and Tween 80 into the drug/oil mixture to promote self-emulsification and thus help to further increase the absorption of tocotrienols; and
(iii) a suitable combination of surfactant system (Labrasol and Tween 80) with the oil/drug mixture to optimize drug absorption.
Accordingly, it is the object of the present invention to provide a novel formulation for fat-soluble drugs that can self-emulsify in aqueous medium with little agitation.
This objective is accomplished by providing,
A pharmaceutical formulation for oral administration which comprises:
(i) a fat-soluble drug;
(ii) an appropriate oil; and
(iii) an appropriate surfactant system;
the resulting formulation which self-emulsifies under gentle agitation in the presence of an aqueous medium.
According to the present invention, there is provided a new formulation of tocotrienols, in which the tocotrienols are incorporated into a palm olein-surfactant system to form a self-emulsifying system. This formulation is made into soft gelatin capsule and in stomach, the contents are released, resulting in the formation of emulsion and therefore increased absorption.